Digoxin, one of the cardiac (or digitalis) glycosides, is known for use in the treatment of congestive heart failure. When administered at the proper therapeutic dosage level, digoxin exerts a direct cardiotonic effect on the myocardium to increase the force of contraction and improve cardiac tone. It has a narrow therapeutic index, i.e. the dose producing the toxic or other undesirable side effects is not much greater than the therapeutically effective dose. Several side effects encountered in the treatment with cardiac glycosides are related to a peak in plasma concentration often occurring a few hours after administration of a dose. Very rapid initial rate of release results in higher peak plasma levels and therefore more side effects. On the other hand, if digoxin is released too slowly from tablets into gastrointestinal fluids then incomplete absorption occurs. The United States Pharmacopoeia [USP XXIV & NF XIX (The United States Pharmacopoeia Convention, Inc., Rockville, Md. 1999)] sets a specification for digoxin tablets requiring that at least 85% digoxin be released in 60 minutes.
German Patent DE 1467788 discloses compositions that contain digoxin in solution, sodium alginate and polyacryahnide for gradual and controlled release of digoxin. The patent relates to a liquid composition and does not teach or disclose the preparation of a tablet dosage form providing the desired release profile of the present invention.
Prior art compositions either relate to improving the solubility or dissolution rate of digoxin to enhance its bioavailability or relates to enteric coated compositions that do not release digoxin in acidic gastric fluids or relate to controlled release of digoxin over much longer periods than stipulated herein in the present invention. Whereas very rapid initial rate of release results in higher plasma level and more side effects, prior art does not discuss or disclose a composition that releases not more than 50% digoxin at 5 minutes when tested in vitro in United States Pharmacopoeia Type I Dissolution apparatus using 500 ml of 0.1N HCl at 120 rpm for 60 minutes at 37° C. The commercial tablets marketed under the name Lanoxin® releases more than 50% digoxin at 5 minutes when tested under these conditions.